There are many different methods that may be used to resolve racemic compounds. The use of enzymes derived from biological systems (for example, from a microorganism or an animal organ) have been particularly useful in the resolution of racemic compounds to form substantially optically pure (enantiomerically enriched) compounds.
In biocatalytic resolution systems, a chiral compound composed of two enantiomers is used as the substrate for the enzyme. The enzyme recognizes and favors only one of the enantiomers as the substrate for the enzymatic reaction. The stereoselectivity of the enzyme optimally affords a product mixture having 50% conversion to a single enantiomer product and 50% recovered substrate of opposite configuration (commonly referred to as an "antipode"). The success of a resolution procedure is determined by the optical purities obtained.
For an enzymatic kinetic resolution, the optical purities of the product and recovered substrate define the degree of enantioselectivity of the reaction and can be expressed as the "E" value. The "E" value is a directly proportional measurement of the R to S reactivity rate ratio, with higher optical purities for product and recovered substrate affording higher "E" values. Because the "E" value is independent of conversion, it is particularly useful in evaluating kinetic resolutions where optical purities can change depending on the extent of reaction. (Chen, C. S., et al., J. Am. Chem. Soc., 1982, 104, p. 7249.)
For present purposes, "substantially optically pure compounds" are enantiomerically enriched compounds defined as having an enantiomeric excess ("ee") value of greater than about 80%.+-.2%. Enantiomeric excess ("ee") is the absolute value of % R minus % S and is used interchangeably with optical purity.
One typical consequence of a biocatalytic resolution process is the 50% maximum yield of each enantiomer. This limitation is particularly problematic if one enantiomer is more useful than its antipode. Frequently, an unwanted antipode is considered a "waste" material.
As with any product mixture resulting from a biocatalytic resolution system, interconversion of the unwanted enantiomer from the product mixture to the desired enantiomer (or at the very least racemization for recycling purposes) would be highly desirable to maximize yield and minimize cost of a useful product. It would be especially useful to develop a method of interconversion having high stereoselectivity to convert one enantiomer to the substantially optically pure antipodal product.
An example of a biocatalytic resolution process in which the interconversion process would be useful, for example, is with preparations involving 3-butene-1,2-diol (shown as structures 1 and 2 below, hereinafter referred to as "BDO"). ##STR1## As BDO is an especially useful chiral synthon, interconversion of the R- and S- BDO enantiomers, shown above as structures 1 and 2, would greatly enhance the versatility and utility of the biocatalytic preparation. The interconversion of BDO must rely in some manner on an inversion of configuration at the allylic carbon of a BDO derivative, most efficiently the corresponding epoxide, epoxybutadiene ("EpB" which may be readily prepared from BDO, or various derivatives, without loss of optical purity). Typically, inversion of configuration is approached using a concerted S.sub.N 2 (nucleophilic) process rather than an S.sub.N 1 process since S.sub.N 1 (ionizing) conditions normally lead to racemization, especially with allylic electrophiles (such as EpB) which afford stabilized carbocations. The allylic nature of EpB, however, presents complications for the inversion processes because three of the four carbons of EpB have significant electrophilic reactivity. Thus, a useful S.sub.N 2 interconversion process for EpB must be both highly stereoselective for inversion and yet regioselective for the chiral (allylic) center.
It is well known that more basic reaction conditions favor S.sub.N 2 processes while S.sub.N 1 reactions are favored at lower pH. (Lowry, T. H. and Richardson, K. S., "Mechanism and Theory in Organic Chemistry," Harper and Row Publishers, New York; 1981, pp.323-330.) The simplest S.sub.N 2 method with a potential for stereoselective inversion of EpB to form BDO is reacting the epoxide with hydroxide ion. However, it has been found that a similar nucleophilic opening of the epoxide of EpB with methoxide under basic conditions proceeds with high regioselectivity for the undesired primary epoxide terminus, thus encouraging retention of configuration. (Parker, R. E.; Isaacs, N. S., Chem. Rev. 1975, p. 737 and Smith, J. G., Synthesis, 1984, p. 629.) Indeed, reaction of S-EpB with sodium hydroxide affords BDO of only 30% ee, indicating significant reactivity at both epoxide carbons.
Although EpB can be opened under neutral or acidic conditions, it is known that as the reaction media becomes more acidic and ionizing, S.sub.N 1 processes (initial ionization) are favored. An S.sub.N 1 reaction would be expected to result in poor stereoselectivity, because once the epoxide opens to the corresponding stabilized allylic carbocation, the epoxide would be expected to rapidly and largely racemize. (Lowry, T. H. and Richardson, K. S. "Mechanism and Theory in Organic Chemistry", Harper and Row Publishers, New York; 1981, pp. 315-320; and Ross, A. M.; Pohl, T. M.; Piazza, K.; Thomas, M.; Fox, B.; Whalen, D. L., J. Am. Chem. Soc., 1982, 104, p. 1658.) Stereochemical scrambling due to the intermediacy of the allylic carbocation in systems closely related to EpB [such as cyclopentadiene monoepoxide (3)] has been observed. As shown below, hydrolysis of cyclopentadiene monoepoxide (3) under acidic conditions affords all four possible products, cis-4, trans-4, cis-5, trans-5 in a ratio of 25:16:16:43, respectively. (Ross, A. M.; Pohl, T. M.1 Piazza, K.; Thomas, M.; Fox, B.; Whalen, D. L. J. Am. Chem. Soc. 1982, 104, p. 1658.) Thus, literature precedent indicates that the hydrolytic opening of vinyl epoxides under S.sub.N 1 conditions is largely stereorandom. ##STR2##
It has also been reported that the product distribution for the opening of EpB under neutral or acidic conditions differs from the product distribution under basic conditions. Acidic conditions result in high regioselectivity for the secondary allylic position, with a small amount of primary allylic product (2-butene-1,4-diol) (Petrov, V. A., et al., Zh. Organ. Khim., 1984, 20, 993.) The presence of only minor amounts of primary allylic products has been suggested as indicative of an A-2-like (bimolecular) transition state. (Ross et al., J. Am. Chem Soc., 1982, 104, 1658.) This, however, may just reflect the relative thermodynamic stabilities of the secondary versus the primary positions and therefore the amount of cationic character at each position. Notwithstanding, the presence of the two allylic products indicates that the transition state involves allylic C-O bond cleavage with a significant amount of carbocation character. Accordingly, an even more thoroughly racemized product than that obtained using basic conditions would be expected when opening acyclic vinyl epoxides using acidic conditions.
Discovering a method for the interconversion of these enantiomeric species while substantially maintaining the optical integrity of the products is needed.